Suicide is a complex phenomenon comprised of biological and psychological risk factors, in addition to social, environmental, and economic contributors. The most consistent of these risk factors is the presence of a psychiatric illness. One of the challenges inherent in developing strategies for suicide prevention is that suicide is a rare and unpredictable event. It is extremel important, therefore, to identify biological markers that are associated with high risk for suicide Family, twin and adoption studies strongly suggest genetic contributions to suicide; furthermore, the genetic predilection for suicide appears to be largely independent of genetic liability to mental illness. To date, many conventional association studies have been performed but have not revealed any genetic variants that could be used as reliable predictors of suicide risk. In thi application we propose using alternate approaches which we expect to be more successful in identifying such predictors. Our first approach, (which will be explored in Specific Aim 1) is related to a rarely studied mechanism of homeostatic plasticity-RNA editing of serotonin 2C receptor (5-HT2CR). Editing can generate many different 5-HT2CR isoforms which vary in their functional activity, thus enabling the 5-HT2CR-expressing neurons to respond to both environmental and genetic perturbations. Our studies, as well as studies in other laboratories, have demonstrated that 5-HT2CR editing is altered in the prefrontal cortex (PFC) of suicide victims regardless of their underlying psychiatric illness. Thus, dysregulation of editing constitutes a biological factor that is strongly associated with completed suicide. 5-HT2CR is expressed at levels that can be reliably assayed only in the brain and spinal cord. Therefore, editing cannot be noninvasively measured in living individuals in the areas relevant to suicide (i.e., PFC). We hypothesize the existence of single nucleotide polymorphisms (SNPs) that are associated with 5-HT2CR editing, and in our preliminary studies we have already identified several such candidate SNPs. Here we aim to confirm these findings and to identify novel editing-associated SNPs in a significantly larger cohort of postmortem specimens (N=583). The editing-associated SNPs can be used as a proxy for measuring editing in the brain, and therefore, as predictors for suicide risk. Our second approach (Specific Aim 2) will be to uncover SNPs that are associated with behavioral traits that constitute susceptibility factors for suicide and are, therefore, considered to represent suicide-related endophenotypes. This strategy allows the deconstruction of suicide into parts that are less etiologically and geneticall heterogeneous. To this end, we will perform genome-wide association studies (GWASs) in a large cohort (N=1,200) of demographically and genetically homogeneous young male conscripts in the Greek Army. For these individuals the results of self-reporting measures and behavioral/psychophysiological assessments of suicide-related phenotypes, as well as genomic DNA specimens, have already been obtained and are available for us. Not all genetic components that are associated with editing or with suicide-related endophenotypes are specifically related to suicide. Therefore, in our last Aim we will determine which of the SNPs identified in Aims 1 and 2 are more likely to represent suicide-specific risk factors. To achieve this goal, we will use (1) large publicly available data sets of GWASs in psychiatric patients with and without a history of attempted suicide and (2) postmortem PFC specimens from psychiatric patients who died of suicide or by other means. When confirmed, the risk alleles could be measured in peripheral blood cells, thus providing biological correlates associated with liability to suicide. Mapping these alleles will also uncover pathways that are altered in the brains of people who are prone to suicidal behavior, hence opening new venues to the understanding of pathophysiology of suicide.